Arphamenine A may be deemed as an optically active derivative of L-arginine, which is produced fermentatively by a microorganism, Chromobacterium violaceus BMG361-CF4 (ATCC 39373). Arphamenine A is the novel substance which was discovered by the present inventors as aminopeptidase-inhibitor and which shows an immunopotentiating activity and an analgesic activity (see Japanese patent application No. 96,276/84; U.S. Pat. No. 4,595,698 and U.S. patent application Ser. No. 809,215).
Arphamenine A is of the chemical structure represented by the following formula ##STR1## During the inventors' extensive researches in an attempt to synthesize arphamenine A and its related compounds, it has now been found that the arphamenine A can be synthesized in a facile way and in a favorable yield by starting from L-arginine, converting it into an iodomethylketone derivative thereof, and reacting the latter with a metal salt derivative of a benzyl-substituted malonic acid diester. Further, it has now been found that the functional groups present in the necessary reactants, namely L-arginine and the malonic acid derivatives employed must be protected by such protective groups which can readily be cleaved under mild reaction conditions with involving neither the racemization at the .alpha.-carbon atom of L-arginine nor the decomposition of the instable guanidino group of L-arginine in the course of carrying out the synthetic process. When an optically active compound of such structure, like the arphamenine A of the formula ##STR2## wherein there exist two asymmetrical carbon atoms, the one in the .alpha.-amino acid residue moiety and the other in the 2-position adjacent to the terminal carboxyl group, which are linked by a ketomethylene group (CO--CH.sub.2 --), is to be synthetized starting frrom an L-.alpha.-amino acid, the drawback is likely to occur that racemization would take place at the .alpha.-carbon atom of the .alpha.-amino acid moiety in the course of the synthetic route, if there is used a method comprising an application of Dakin-West reaction using a ketomethylene compound and oxazolone, followed by hydrolysis under strong acidic conditions (see "Journal of Medicinal Chemistry" Vol. 24, page 964 (1981)), or alternatively a method comprising reacting a Grignard reagent with an ester of an amino acid with pyridine-thiol (see "Tetrahedron Letter" Vol. 23, page 2533 (1982)). Further, the former method using the Dakin-West reaction is disadvantageous not only in that the necessary starting ketomethylene compound, namely a half-ester or half-acid chloride of succinic acid derivative is difficult to prepare, but also in that the intermediate condensation product whose the amino group has been acylated is formed, with the consequence that the deprotection of the N-acyl group in the last stage requires a hydrolysis under strong acidic conditions. Besides, the latter method using the Grignard reaction is also disadvantageous not only in that the starting compound as needed can be chosen only within a limited scope of compound because of the required use of the Grignard reagent, but also in that the reaction procedures involved are troublesome, for example, owing to the need for protection of the ketone group in the starting compound.
An object of this invention is to provide a process of synthesizing arphamenine A, which can be operated in a facile way nd at a higher yield of arphamenine A of a highly pure, optically active form, than when using the prior art methods as mentioned above. Another objects of this invention will be clear from the following descriptions.